Schizophrenia is one of the most debilitating psychiatric disorders, affecting approximately 1% of the population worldwide. A number of antipsychotic drugs are available but these are often ineffective and do not treat all the symptoms of the disease. New therapeutics are needed but their discovery has been hampered by a limited understanding of the etiology of this complex neurological disorder, and a lack of clear understanding of the precise molecular mechanisms of action of available antipsychotic drugs. One of the major limitations in identifying the molecular mechanisms of antipsychotic drug action has been the heterogeneous and intermixed cellular nature of the central nervous system. The major goal of the proposed studies in the Conte Center is therefore to achieve a complete understanding of the cellular and molecular actions of antipsychotic drugs through innovative approaches that use novel rodent animal models to allow analysis of individual types of neurons within cortico-striatal circuits. The Center Director and leader of Project 1 is Paul Greengard (Rockefeller University). The other Project leaders are: Nathaniel Heintz (Project 2, Rockefeller University); Angus Nairn (Project 3, Yale University); Eric Nestler (Project 4, Mount Sinai Medical School); and James Surmeier (Project 5, Northwestern University. There will also be an Animal Core, a Molecular & Biochemical Reagents Core, and an Administrative Core. The five Pis involved have an established history of effective collaboration and will use their complementary expertise and resources to take a multi-disciplinary approach in the proposed research. Through the use of biochemical, cell biological, molecular, electrophysiological, structural and behavioral assays, the proposed Conte Center will achieve a fuller understanding of the cellular and molecular actions of antipsychotic drugs in the cortico-striatal circuits. PUBLIC HEALTH RELEVANCE: Relevance to public health: Schizophrenia is a debilitating psychiatric disorder, and new therapies are needed. This Conte Center will characterize the effects of antipsychotic drugs on the properties of specific neuronal subtypes involved in schizophrenia, allowing for a complete understanding of the normal and maladaptive actions of these drugs, and leading to better therapies with higher efficacy and fewer side-effects.